Articles
Assessment of the Xpert MTB/RIF assay for diagnosis of tuberculosis with gastric lavage aspirates in children in sub-Saharan Africa: a prospective descriptive study

https://doi.org/10.1016/S1473-3099(12)70245-1Get rights and content

Summary

Background

Rapid and accurate diagnosis of pulmonary tuberculosis in children remains challenging because of difficulties in obtaining sputum samples and the paucibacillary nature of the disease. The Xpert MTB/RIF assay is useful for rapid diagnosis of childhood tuberculosis with sputum and nasopharyngeal samples. We assessed this assay for the detection of tuberculosis and multidrug resistant (MDR) tuberculosis with gastric lavage aspirate (GLA) samples in children admitted to hospital.

Methods

We did a prospective study to assess the sensitivity and specificity of the Xpert MTB/RIF assay with GLA samples for the detection of pulmonary tuberculosis and MDR tuberculosis in new paediatric inpatient admissions at the University Teaching Hospital, Lusaka, Zambia. Children aged 15 years or younger were recruited between June, 2011, and May, 2012. GLA and sputum were analysed by standard smear-microscopy, mycobacterial growth indicator tube (MGIT) culture, MGIT drug-susceptibility testing, and the Xpert MTB/RIF assay. Sensitivity of the Xpert MTB/RIF assay was assessed with the Pearson χ2 or Fishers exact test.

Findings

Of 930 children, 142 produced sputum and GLA was obtained from 788 non-sputum producers. Culture-positive tuberculosis was identified in 58 (6·2%) of 930 children: ten from sputum producers and 48 from GLA of non-sputum producers. The sensitivity and specificity of the Xpert MTB/RIF assay were similar: sensitivity was 68·8% (95% CI 53·6–80·9) for GLA versus 90·0% (54·1–99·5; p=0·1649) for sputum samples; specificity was 99·3% (98·3–99·8) for GLA and 98·5% (94·1–99·7; p=0·2871) for sputum samples. The Xpert MTB/RIF assay detected an extra 28 tuberculosis cases compared with smear microscopy and was significantly more sensitive than smear microscopy for both sputum (90·0% [54·1–99·5] vs 30·0% [8·1–64·6], p=0·01) and GLA (68·8% [53·6–80·9] vs 25·0% [14·1–40·0], p<0·0001). The assay load did not differ significantly by sample type (p=0·791). 22 children were infected with HIV and tuberculosis and significant differences in assay performance could not be detected when stratifying by HIV status for either sample type. The Xpert MTB/RIF assay detected rifampicin resistance in three GLA samples: two confirmed as MDR tuberculosis and one false positive.

Interpretation

Analyses of GLA samples with the Xpert MTB/RIF assay is a sensitive and specific method for rapid diagnosis of pulmonary tuberculosis in children who cannot produce sputum. The single site nature of our study invites caution.

Funding

European Commission, European Developing Countries Clinical Trials Partnership, and UBS Optimus Foundation.

Introduction

WHO estimates the global burden of tuberculosis at 9 million new cases a year, with up to 15% of the burden in children.1 In sub-Saharan Africa, an estimated 20% of all cases of active pulmonary tuberculosis are in children.2, 3, 4 Currently available diagnostic techniques are insufficient for the rapid and accurate diagnosis of tuberculosis and multidrug resistant (MDR) tuberculosis (ie, tuberculosis caused by strains of Mycobacterium tuberculosis resistant to at least isoniazid and rifampicin) in children in countries highly endemic for tuberculosis and HIV.5, 6, 7, 8, 9 In such settings sputum microscopy is often the only test available. This test performs poorly in children for several reasons: the inability of young children to expectorate sputum, the paucibacillary nature of sputum from those co-infected with HIV, and inability to identify MDR tuberculosis.2 Where optimum culture facilities are available, confirmation is delayed and the combination of sputum smear and culture tests still miss many cases of childhood tuberculosis.10

Tertiary referral hospitals in sub-Saharan Africa have a high inpatient load of children admitted to paediatric wards with respiratory illnesses, many of whom die of undiagnosed pulmonary tuberculosis.11, 12 A large burden of tuberculosis in children is evident at all points of the health-care system in sub-Saharan Africa, emphasising an urgent need to develop, assess, and introduce more rapid and accurate diagnostics and diagnostic algorithms for childhood tuberculosis. In December, 2010, WHO endorsed the Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA, USA) for rapid diagnosis of tuberculosis and MDR tuberculosis with sputum in regions highly endemic for tuberculosis and HIV.13 Several studies have assessed the Xpert MTB/RIF assay in adults with pulmonary tuberculosis in sub-Saharan Africa and a meta-analysis of 16 studies gave a pooled sensitivity of 90% and a pooled specificity of 98%.14 In an inpatient hospital setting, the assay can identify the M tuberculosis complex and simultaneously detect rifampicin resistance in sputum samples from adult patients operationally within 24 h.15

Recent studies investigating the Xpert MTB/RIF assay for diagnosis of pulmonary tuberculosis in children using sputum samples in Cape Town, South Africa,16, 17 and Mbeya, Tanzania,18 have suggested that the assay is better than sputum-smear microscopy. A major hindrance in the assay's application for diagnosis of childhood tuberculosis is the inability of a large proportion of children with pulmonary tuberculosis to expectorate sputum. In these children, the Xpert MTB/RIF assay has proven useful with induced sputum.16, 17, 18 A recent study by Zar and colleagues17 showed that testing two nasopharyngeal aspirates in children with suspected pulmonary tuberculosis with the Xpert MTB/RIF assay can be useful, especially in settings where facilities for inducing sputum and culture are not available. Further assessment of the assay in children from settings with high burdens of tuberculosis and HIV, with specimens other than sputum, are warranted.

Zambia has a high incidence of tuberculosis (462 cases per 100 000 population) and a high HIV prevalence (13·5%).19 Only 6% of reported cases of childhood tuberculosis are sputum-smear positive, with the remaining cases diagnosed on the basis of clinical criteria. Furthermore, no data exist on the prevalence of MDR tuberculosis in children in Zambia. Tertiary care hospitals in sub-Saharan Africa receive many seriously ill children with communicable and non-communicable diseases with HIV and M tuberculosis co-infection. Many of these children harbour active tuberculosis but remain undiagnosed.20

We sought to assess the Xpert MTB/RIF assay with gastric lavage aspirate (GLA) samples for the rapid diagnosis of active pulmonary tuberculosis and MDR tuberculosis in children.

Section snippets

Study design and patients

We did a prospective study to assess the performance of the Xpert MTB/RIF assay with GLA samples for the detection of pulmonary tuberculosis and MDR tuberculosis in new paediatric inpatient admissions at the Department of Paediatric and Child Health, University Teaching Hospital, Lusaka, Zambia—a tertiary referral centre serving an urban population of about 1·2 million people from Lusaka province of whom about 40% are children. The hospital admits patients who present acutely to the accident

Results

1037 children were recruited and had sputum or GLA obtained for analysis (figure 1). About half (516; 49·8%) of children enrolled were younger than 2 years (median 24 months; IQR 12–74) and did not differ by HIV prevalence, which was 30·5%.

Some children were excluded from our assessment of the performance of the Xpert MTB/RIF assay (figure 1). We were able to obtain GLAs from all children who could not produce sputum. 431 children (46·3%) had suspected tuberculosis on admission, 488 (52·5%) did

Discussion

Our study prospectively assesses the Xpert MTB/RIF assay for the rapid diagnosis of childhood tuberculosis using GLA samples in a high tuberculosis and HIV endemic setting. The study has four key findings: the Xpert MTB/RIF assay performs well in GLA samples for rapid and accurate diagnosis of childhood tuberculosis; no significant difference was evident in the accuracy of the assay between sputum and GLA samples, although a larger study would be needed to confirm this finding—ideally with

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